Outcome In Advanced Gastric Cancer Patients Research Articles

Expression of p53 as a biomarker in determining response to apatinib for advanced gastric cancer.

Apatinib has shown outstanding value in the treatment of advanced gastric cancer (AGC). However, no biomarkers are available to select AGC patients who will benefit from apatinib. The aim of the present study was to investigate the association between p53 and Ki67 expression of and the outcome in AGC patients treated with apatinib. From December 2015 to December 2020, 92 AGC patients were enrolled and was retrospectively evaluated. They were given apatinib at a daily dose of 500 or 250 mg every 4 weeks to monitor clinical efficacy and adverse events (AEs). Kaplan-Meier method was used for survival analysis. Expression of p53 and Ki67 was detected by immunohistochemistry (IHC) and correlated with survival. Among 92 evaluable patients, the objective response rate (ORR) and disease control rate (DCR) were 17.4% and 79.3%, respectively, and none of them achieved a CR, 16 achieved a PR (17.4%) (95% CI 9.8%-26.1%). Stable disease (SD) was observed in 57.6% of patients (95% CI 49.2%-69.9%) and PD in 21.7% of patients (95% CI 13.6%-31.3%). The median progression free survival (mPFS) was 122.7 ± 8.2 days, and the median overall survival (mOS) was 203.4 ± 11.9 days. P53 expression was observed in 35 patients (38.0%) and high expression of Ki67 was detected in 34 patients (37.0%). There was a statistically significant inverse relationship between p53 and Ki67 expression (P=0.014). Moreover, p53 was significantly correlated with the OS (P=0.018), but Ki67 had no significant influence on OS. Apatinib showed promising efficiency and was well tolerated as a second-line treatment for AGC patients. AGC patients with p53-negative were likely to benefit from apatinib treatment; however, the expression of Ki67 proteins has no significant impact on the outcome of AGC patients.

Intratumoral CD8+ t cell as a potential positive predictor for treatment of chemo-immunotherapy in PD-L1 negative advanced gastric cancer patients.

e16029 Background: It was demonstrated that CPS PDL1 positive patients of advanced gastric cancer (GC) could benefit from specific immune checkpoint inhibitors (ICI) for first-line, and second-line or subsequent therapy. However, whether the application of ICI could lead to better clinical outcome in advanced GC patients who were negative for PDL1 remains further explore. Some studies showed that patients with specific tumor immune microenvironment (TME) are more sensitive to immunotherapy. Therefore, TME may be a potential positive predictor for PDL1 negative patients treated with immunotherapy. Methods: We retrospectively enrolled 26 advanced GC patients who were treated by chemoimmunotherapy in Shenzhen Hospital of Peking University and evaluated for clinical characteristics. Peritumoral and intratumoral Tumour-infiltrating lymphocytes (TIL) were detected by mIHC (multiplex immunofluorescence) among these patients. The correlation between PFS and clinical characteristics including TIL was analyzed by univariate survival analysis and multivariate Cox proportional hazards analysis. Results: In 26 patients, 5 patients (19.2%) experienced complete response (CR), 9 patients (34.6%) experienced partial response (PR), while 7 patients (26.9%) experienced stable disease (SD). Compared with non-responders, higher intratumoral infiltrating CD8+ T cells instead of other subtypes were detected in CPS PDL1 negative Patients who respond to chemoimmunotherapy. Further analysis revealed that CD8+ TIL was a predictive biomarker for PFS to chemo-immunotherapy in CPS PDL1 negative patients. Conclusions: For CPS PDL1 negative advanced GC patients, intratumoral CD8+ TIL may be a potential positive predictor for treatment of chemo-immunotherapy.

Laparoscopic vs open total gastrectomy for advanced gastric cancer following neoadjuvant therapy: A propensity score matching analysis

BACKGROUNDLaparoscopic total gastrectomy (LTG) has drawn increasing attention over the years. Although LTG has shown surgical benefits compared to open TG (OTG) in early stage gastric cancer (GC), little is known about the surgical and oncological outcomes of LTG for advanced GC following neoadjuvant therapy (NAT).AIMTo compare the long- and short-term outcomes of advanced GC patients who underwent LTG vs OTG following NAT.METHODSAdvanced GC patients who underwent TG following NAT between April 2011 and May 2018 at the Cancer Hospital of the Chinese Academy of Medical Sciences were enrolled and stratified into two groups: LTG and OTG. Propensity score matching analysis was performed at a 1:1 ratio to overcome possible bias.RESULTSIn total, 185 patients were enrolled (LTG: 78; OTG: 109). Of these, 138 were paired after propensity score matching. After adjustment for propensity score matching, baseline parameters were similar between the two groups. Compared to OTG, LTG was associated with a significantly shorter length of hospital stay (P = 0.012). The rates of R0 resection, lymph node harvest, and postoperative morbidity did not significantly differ between the two groups. Overall survival (OS) outcomes were comparable between the two groups. Pathological T and N stages were found to be independent risk factors for OS.CONCLUSIONLTG can be a feasible method for advanced GC patients following NAT, as it appears to be associated with better short- and comparable long-term outcomes compared to OTG.

Decrease in Blood Neutrophil-to-Lymphocyte Ratio Indicates Better Survival After Neoadjuvant Chemotherapy in Patients With Advanced Gastric Cancer.

Introduction: Gastric cancer is the fifth most commonly diagnosed tumor and is the fourth leading cause of cancer-related mortality, worldwide. Due to the low rate of early diagnosis, approximately two-thirds of patients are first diagnosed at an advanced stage. Neoadjuvant chemotherapy (NAC) is recommended for patients with advanced gastric cancer (AGC). The neutrophil-to-lymphocyte ratio (NLR), a combined inflammatory and immunogenic factor, has been universally used for predicting outcomes in AGC patients. Given that NLR is a dynamic process, in this study, we investigated the value of NLR change for the prediction of chemotherapeutic responses and prognosis in patients with AGC.Methods: We retrospectively enrolled 111 patients with AGC who underwent NAC following curative surgery. Patients were divided into two groups according to the NLR change after chemotherapy into the increased and decreased groups. Outcome measures were overall survival (OS) and disease-free survival (DFS). Univariate was calculated by Kaplan-Meier method. Multivariate analysis was performed using the Cox proportional hazards regression model.Results: Post-chemotherapy, NLR increased in 36 patients and decreased in 75 patients. After a median follow-up time of 19 months, six patients developed local recurrence, 23 developed distant recurrence, and 34 died. Patients with reduced post-chemotherapy NLR showed significantly longer OS (p < 0.001) and DFS (p < 0.001). A decrease in the NLR after NAC was an independent indicator associated with better OS (p < 0.001) and DFS (p < 0.001).Conclusions: In patients with AGC, a decrease in NLR after NAC indicated better survival. NLR change could serve as a robust indicator for the efficiency of NAC and prognostic prediction in patients with AGC.

Combined Neutrophil-to-Lymphocyte and Platelet-Volume-to-Platelet Ratio (NLR and PVPR Score) Represents a Novel Prognostic Factor in Advanced Gastric Cancer Patients.

Background: Chemotherapy is a cornerstone of treatment in advanced gastric cancer (GC) with a proven impact on overall survival, however, reliable predictive markers are missing. The role of various inflammatory markers has been tested in gastric cancer patients, but there is still no general consensus on their true clinical applicability. High neutrophil-to-lymphocyte (NLR) and low (medium)-platelets-volume-to-platelet ratio (PVPR) are known markers of unspecific immune system activation, correlating significantly with outcomes in advanced GC patients. Methods: Metastatic GC patients (N:155) treated with chemotherapy +/− trastuzumab were enrolled in this retrospective study. Pre-treatment NLR and PVPR, as well as other inflammatory markers were measured in peripheral blood. Univariate Cox regression was conducted to find markers with a significant impact on overall survival (OS) and progression-free survival (PFS). Spearman correlation and Cohen’s kappa was used to analyze multicollinearity. Multiple multivariable Cox regression models were built to study the combined impact of NLR and PVPR, as well as other known prognostic factors on OS. Results: Elevated NLR was significantly associated with increased risk of death (HR = 1.95; 95% CI: 1.17–3.24), and lower PVPR was significantly associated with improved outcomes (HR = 0.53; 95% CI: 0.32–0.90). A novel inflammatory marker, based on a combination of NLR and PVPR, allows for the classification of GC patients into three prognostic groups, characterized by median OS of 8.4 months (95% CI 5.8–11.1), 10.5 months (95% CI 8.8–12.1), and 15.9 months (95% CI 13.5–18.3). Conclusion: The NLR and PVPR score (elevated NLR and decreased PVPR) is a marker of detrimental outcome of advanced GC patients treated with chemotherapy.

Prospective evaluation of metabolic intratumoral heterogeneity in patients with advanced gastric cancer receiving palliative chemotherapy

Although metabolic intratumoral heterogeneity (ITH) gives important value on treatment responses and prognoses, its association with treatment outcomes have not been reported in gastric cancer (GC). We aimed to evaluate temporal changes in metabolic ITH and the associations with treatment responses, progression-free survival (PFS), and overall survival (OS) in advanced GC patients. Eighty-five patients with unresectable, locally advanced, or metastatic GC were prospectively enrolled before the first-line palliative chemotherapy and underwent [18F]FDG PET at baseline (TP1) and the first response follow-up evaluation (TP2). Standardized uptake values (SUVs), volumetric parameters, and textural features were evaluated in primary gastric tumor at TP1 and TP2. Of 85 patients, 44 had partial response, 33 had stable disease, and 8 progressed. From TP1 to TP2, metabolic ITH was significantly reduced (P < 0.01), and the degree of the decrease was greater in responders than in non-responders (P < 0.01). Using multiple Cox regression analyses, a low SUVmax at TP2, a high kurtosis at TP2 and larger decreases in the coefficient of variance were associated with better PFS. A low SUVmax at TP2, larger decreases in the metabolic tumor volume and larger decreased in the energy were associated with better OS. Age older than 60 years and responders also showed better OS. An early reduction in metabolic ITH is useful to predict treatment outcomes in advanced GC patients.

Role of Cancer-Associated Fibroblast in Gastric Cancer Progression and Resistance to Treatments.

Although the survival of gastric cancer (GC) patients has gradually improved, the outcomes of advanced GC patients remain unsatisfactory despite standard treatment with conventional chemotherapy or targeted agents. Several studies have shown that cancer-associated fibroblasts (CAFs), a major component of tumor stroma in GC, may have significant roles in GC progression and resistance to treatments. CAFs are a major source of various secreted molecules in the tumor microenvironment, which stimulate cancer cells and other noncancerous components of GC. Surprisingly, these factors could be involved in gastric carcinogenesis. Cytokines, including interleukin-6 and interleukin-11, or growth factors, such as fibroblast growth factor produced from CAFs, can directly activate GC cells and consequently lead to the development of an aggressive phenotype. Galectin-1 or hepatocyte growth factor can be involved in CAF-derived neovascularization in GC. In addition, recent studies showed that CAFs can affect tumor immunity through M2 polarization of tumor-associated macrophages. Finally, the current study aimed to introduce several inhibitory agents and evaluate their suppressive effects on CAFs in patients with GC progression. However, further studies are required to evaluate their safety and select appropriate patients for application in clinical settings.

Associations between early tumor shrinkage and depth of response and clinical outcomes in patients treated with 1st-line chemotherapy for advanced gastric cancer.

Although early tumor shrinkage (ETS) predictions of the efficacy and depth of response (DpR) reflects clinical outcomes in chemotherapy with epidermal growth factor receptor inhibitor regimens to treat metastatic colorectal cancer, their value in assessing treatments for advanced gastric cancer (AGC) is unclear. Here we evaluated relationships between ETS and DpR and clinical outcomes in AGC patients treated with first-line chemotherapy. We retrospectively enrolled 612 consecutive patients treated with first-line chemotherapy for AGC between January 2010 and June 2016. ETS and DpR were defined as changes from baseline in summed longest diameters in target lesions at 8 (±4) weeks for ETS and at the smallest observed volume for DpR. Eligible patients were sorted into HER2+ (n=100) and HER2- (n=186) groups. Median follow-up was 14.8months. The overall response rate and disease control rates were 64 and 87% in the HER2+ group and 53.2 and 86.0% in the HER2- group. Respective median PFS and OS were HER2+: 7.9 and 20.8months and HER2-: 6.6 and 13.8months. The respective ETS rate and median DpR were HER2+: 70 and 44% and HER2-: 57.5 and 24%. Clinical outcomes and ETS/DpR were correlated, especially in the HER2+ group (OS: P<0.0001; PFS: P<0.0001). In multivariate analysis, ETS was an independent predictor for OS in the HER2+ group and for PFS in both groups. These results indicate that ETS may be an early-on treatment predictor of the efficacy of HER2+ advanced gastric cancer treated with first-line chemotherapy that includes trastuzumab.

Influence of TS and ABCB1gene polymorphisms on survival outcomes of 5‑FU-based chemotherapy in aChinese population of advanced gastric cancer patients.

To investigate the impacts of gene variations on survival outcomes of advanced gastric cancer (AGC) patients treated with 5‑fluorouracil (5-FU)-based chemotherapy, we analyzed the associations of 2 indels of the TS gene rs34743033 (double or triple tandem repeats of a28 bp sequence in 5'-UTR, denoted as 2R or 3R allele) and rs16430 (a6 bp variation at 1494 bp in 3'-UTR, denoted as ins6 or del6allele) and 2 single nucleotide polymorphisms (SNPs) of ABCB1gene rs2032582 in exon21 and rs1045642 in exon26, with clinical outcomes after 5‑FU treatment. Generally, indels rs34743033 and rs16430 were genotyped by PCR and polyacrylamide gel electrophoresis assay and SNPs rs2032582 and rs1045642 were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay in 110Chinese AGC patients post-chemotherapy. Cox regression analysis was used to analyze the risk factors affecting patient survival. As aresult, rs34743033, rs1045642 and rs2032582 were shown to be significantly associated with overall survival (P< 0.05), and associations between the four polymorphisms with disease-free survival were also observed (P< 0.05). Moreover, we found that genotypes rs34743033 3R/2R, rs16430 ins6/del6, rs1045642 CC or CT, and rs2032582GG were beneficial predictors of clinical treatment outcome in AGC patients, suggesting some clinical implications in chemotherapy of aChinese population.

O1-13-3 - Outcomes in 50 Patients with Advanced Gastric Cancer Treated in Phase I Trials: the Ncche Experience

Background: Patients with advanced gastric cancer (AGC) have a poor prognosis once standard therapies fail. This retrospective study presents the characteristics and outcomes in AGC patients treated in phase I trials in our institution.Methods: We retrospectively reviewed the clinical outcomes in 50 consecutive patients with AGC who were treated in phase I trials after standard chemotherapies between March 2008 and November 2013.Results: Median age was 65 years (range, 28-74 years) and all had performance status ECOG 0 or 1. The median number of previous systemic chemotherapy was 3 (range, 2-6) with the median interval from beginning of first-line chemotherapy to enrollment for phase I trials of 17 months. Ten patients were enrolled for two or more phase I trials. The median time to treatment failure (TTF) of the best phase I treatment was shorter than those of the last line of systemic chemotherapy (1.4 vs. 2.3 months; HR 1.73; P = 0.01). TTF of best phase I trial was longer than the last line of systemic chemotherapy in 15 patients (30%). Objective response was observed in 4 patients (8%) and additional 5 patients (10%) achieved stable disease >3 months. Severe adverse events and grade >3 toxicities were reported in 8 patients (16%) and 10 patients (20%), respectively. No treatment related death was observed. Median survival time after enrollment for phase I trials was 5.8 months and 3 death (6%) within 30 days after last administration was observed.Conclusions: The median TTF of AGC patients in phase I treatment was shorter than those of their last line of systemic chemotherapy. Although it offer some clinical benefit for small subset of AGC patients after all standard chemotherapy, better studies might be necessary to improve its outcome.

Targeted therapy in the management of advanced gastric cancer: are we making progress in the era of personalized medicine?

Gastric cancer is one of the leading causes of cancer death. With greater understanding of the molecular basis of carcinogenesis, targeted agents have led to a modest improvement in the outcome of advanced gastric cancer (AGC) patients. We conducted an overview of the published evidence regarding the use of targeted therapy in AGC patients. Thus far, the human epidermal growth factor receptor (HER) pathway, angiogenic pathway, and phosphatidylinositol-3-kinase (PI3K)-Akt-mammalian target of rapamycin pathway have emerged as potential avenues for targeted therapy in AGC patients. The promising efficacy results of the Trastuzumab for Gastric Cancer trial led to the approved use of trastuzumab-based therapy as first-line treatment for patients with HER-2+ AGC. On the other hand, the Avastin® in Gastric Cancer trial evaluating bevacizumab in combination with chemotherapy did not meet its primary endpoint of a longer overall survival duration despite a significantly higher response rate and longer progression-free survival time in patients in the bevacizumab arm. Phase III data are awaited for other targeted agents, including cetuximab, panitumumab, lapatinib, and everolimus. Recent progress in targeted therapy development for AGC has been modest. Further improvement in the outcome of AGC patients will depend on the identification of biomarkers in different patient populations to facilitate the understanding of gastric carcinogenesis, combining different targeted agents with chemotherapy, and unraveling new molecular targets for therapeutic intervention.

Anemia is the strongest prognostic factor for outcomes of 5-fluorouracil-based first-line chemotherapy in patients with advanced gastric cancer

To examine the prevalence of anemia and its impact of hemoglobin (Hgb) levels in predicting outcomes of 5-fluorouracil (FU)-based first-line chemotherapy for patients with advanced gastric cancer (AGC). We collected data retrospectively from 511 consecutive patients treated with FU-based first-line chemotherapy as a routine clinical practice for AGC and followed up in two centers from 1995 to 2003. FU was given in combination with cisplatin (61%), taxanes (12%), anthracyclines (24%) and/or folinic acid (50%). Hgb values were <10 g/dl in 41%, and patients with baseline Hgb levels <10 g/dl had significantly lower response rates (9%) than patients with Hgb > or = 10 g/dl (53%; P < 0.001). In addition, Hgb < 10 g/dl served as a predictor for disease progression (RR, 1.77; 95% CI, 1.42-2.21) and death (RR, 1.85; 95% CI, 1.48-2.32) along with chemotherapy response and performance status. Low baseline Hgb level is a strong and independent prognostic factor for the outcomes of AGC patients receiving FU-based first-line chemotherapy. This results strongly suggest that Hgb level, along with performance status, may be considered as a stratification variable in subsequent studies of AGC.